Sustained release of propranolol hydrochloride based on ion-exchange resin entrapped within polystyrene microcapsules

Propranolol-HCl, a water soluble drug, was bound to Indion 254®, a cation exchange resin, and the resulting resinate was microencapsulated with polystyrene using an oil-in-water emulsion-solvent evaporation method with a view to achieve prolonged drug release in simulated gastric and intestinal fluid. The effect of various formulation parameters on the characteristics of the microcapsules was studied. The diameter of the resinate-loaded polystyrene microcapsules increased with increase in the concentration of emulsion stabilizer and coat/core ratio and decreased with increase in the volume of organic disperse phase. The variation in the size of the microcapsules appeared to be related with the inter-facial viscosity which was influenced by the viscosity of both the aqueous dispersion medium and the organic disperse phase. The resinate encapsulation efficiency and hence the drug entrapment efficiency of the microcapsules increased with increase in the concentration of emulsion stabilizer and coat/core ratio and decreased with increase in the volume of organic disperse phase. These characteristics were found to depend on the extent of formation of fractured microcapsules and subsequent partitioning of the resinate into the aqueous dispersion medium. The degree of fracture on the microcapsules depended on the viscosity of the aqueous dispersion medium and the organic disperse phase. The uncoated resinate discharged the drug quite rapidly following the typical particle diffusion process. Although the desorption of the drug from the resinate was independent of pH of the dissolution media, increase in ionic strength increased the drug desorption. On the other hand, release of drug from the coated resinate was considerably prolonged and followed a diffusion controlled model. The prolongation of drug release was dependent on the uniformity of coating which was influenced by the formulation parameters. The drug release from the microcapsules was also found to be independent of pH of the dissolution media and increased with increase in ionic strength. The pH-independent release of the drug from both the uncoated and microencapsulated resinate was due to pH-independent solubility of the drug and high equilibrium concentration of the resinate in both the dissolution media. Polystyrene appeared to be a suitable polymer to provide prolonged release of propranolol independent of pH of the dissolution media.     

Microencapsulation of phenylpropanolamine to achieve sustained release

Phenylpropanolamine HCl was initially microencapsulated with cellulose acetate butyrate, however, the microcapsules did not show acceptable sustained release. A reduction of the drug particle size prior to microencapsulation resulted in a reduction in drug release rate from the microcapsules. The desired drug release profile was attained only when the drug powder was replaced with a drug-resin complex in the microencapsulation process. The pH of the dissolution media had an effect on the drug release profile.     

Preparation and evaluation of ethylcellulose microcapsules of indomethacin

Indomethacin was microencapsulated with ethylcellulose using a modified spherical agglomeration process, aiming at a sustained release preparation without side effects on the stomach. The surface morphology of the microcapsules was examined using scanning electron microscopy. The microcapsules were porous and spherical, and their porosity increased with increasing the viscosity of ethylcellulose.In vitro dissolution process followed Higuchi’s diffusion model for first 3 hr. Release rate of the drug from microcapsules decreased as the viscosity of ethylcellulose or the weight ratio of indomethacin to ethylcellulose was decreased. The release rate also decreased with increasing the microcapsule size. The microcapsules induced less gastric ulcer in rats than raw drug.     

Use of ion-exchange resins to prepare 100 microm-sized microcapsules with prolonged drug-release by the Wurster process

Ion-exchange resin (IER)--drug complexes were used as core materials to explore their capability to prepare a 100 microm-sized, highly drug-incorporated microcapsule with a prolonged drug release by the Wurster process. Diclofenac sodium was loaded into Dowex 1-X2 fractionated into 200--400 mesh and subsequently microencapsulated with two types of aqueous colloidal polymer dispersion, Aquacoator Eudragit RS30D. The mass median diameter and drug content of the microcapsules thus obtained were 98 microm and 46% with Aquacoat, and 95 microm and 50% with Eudragit RS30D, respectively. Each microcapsule was obtained at a product yield of 94%. The rate of drug release from the microcapsules was highly dependent on the encapsulating materials. For the microcapsules coated with Aquacoat, diclofenac sodium was found to be rapidly released over 4 h, even at a 25 wt% coating level because of cracks on the microcapsule surfaces resulting from the swelling stress of the drug-loaded IER cores. In contrast, significantly prolonged drug-release was achieved in the microcapsules prepared with Eudragit RS30D: even such a very low coating level as 3 wt% provided an exceptionally prolonged drug-release over 24 h. The results indicated that the use of IER along with a flexible coating material would be a feasible way to prepare a prolonged release type of microcapsules with a diameter of 100 microm and a drug content of more than 50% by the Wurster process.     

Development and evaluation of polyethyleneimine-treated calcium alginate beads for sustained release of diltiazem

The objective of this investigation is to develop a multi-unit sustained release dosage form of a water soluble drug from a completely aqueous environment avoiding the use of any organic solvent. The drug was complexed with resin and calcium alginate or polyethyleneimine-treated calcium alginate beads loaded with the resinate were prepared by a ionic/polyelectrolyte complexation method. The effect of different formulation variables on the characteristics of the beads was investigated. Although the drug release from spherical and smooth-surfaced calcium alginate beads in both acidic and alkaline dissolution media were slower than those obtained from plain resinate, none of the variables were found to prolong the drug release considerably due to rapid swelling and disintegration of calcium alginate beads in alkaline medium. On the other hand, drug release from polyethyleneimine-treated calcium alginate beads in acidic medium did not increase appreciably following a burst release. However, in alkaline medium, the drug release was found to increase gradually and extend over a different period of time depending on the intensity of polyethyleneimine treatment. Scanning electron micrographs revealed the formation of a dense membrane around the resinate-loaded calcium alginate matrix. The membrane appeared to be responsible for reduced swelling and protracted disintegration of the beads resulting in slow release of the drug. The results indicate that sustained release of a water soluble drug from polyethyleneimine-treated calcium alginate beads could be achieved by adjusting the formulation variables.     

Development and evaluation of polyethyleneimine-treated calcium alginate beads for sustained release of diltiazem

The objective of this investigation is to develop a multi-unit sustained release dosage form of a water soluble drug from a completely aqueous environment avoiding the use of any organic solvent. The drug was complexed with resin and calcium alginate or polyethyleneimine-treated calcium alginate beads loaded with the resinate were prepared by a ionic/polyelectrolyte complexation method. The effect of different formulation variables on the characteristics of the beads was investigated. Although the drug release from spherical and smooth-surfaced calcium alginate beads in both acidic and alkaline dissolution media were slower than those obtained from plain resinate, none of the variables were found to prolong the drug release considerably due to rapid swelling and disintegration of calcium alginate beads in alkaline medium. On the other hand, drug release from polyethyleneimine-treated calcium alginate beads in acidic medium did not increase appreciably following a burst release. However, in alkaline medium, the drug release was found to increase gradually and extend over a different period of time depending on the intensity of polyethyleneimine treatment. Scanning electron micrographs revealed the formation of a dense membrane around the resinate-loaded calcium alginate matrix. The membrane appeared to be responsible for reduced swelling and protracted disintegration of the beads resulting in slow release of the drug. The results indicate that sustained release of a water soluble drug from polyethyleneimine-treated calcium alginate beads could be achieved by adjusting the formulation variables.     

A comparative in vitro assessment of the drug release performance of pH-responsive polymers for ileo-colonic delivery

The aim of this study was to investigate the in vitro dissolution characteristics of pH-responsive polymers in a variety of simulated fluids. Prednisolone tablets were fabricated and coated with the following polymer systems: Eudragit S (organic solution), Eudragit S (aqueous dispersion), Eudragit FS (aqueous dispersion) and Eudragit P4135 (organic solution). Dissolution tests were conducted using a pH change method whereby tablets were transferred from acid to buffer. Three different buffer media were investigated: two compendial phosphate buffers (pH range 6.8-7.4) and a physiological buffer solution (Hanks buffer) with very similar ionic composition to intestinal fluid (pH 7.4). There was considerable drug release from tablets coated with Eudragit P4135 in acid, prompting discontinuation of further investigations of this polymer. Eudragit S (organic solution), Eudragit S (aqueous dispersion) and Eudragit FS on the other hand prevented drug release in acid, though subsequent drug release in the buffer media was found to be influenced by the duration of tablet exposure to acid. At pH 7.4 drug release rate from the polymer coated tablets was similar in the two compendial media, however in the physiological buffer, they were found to differ in the following order: Eudragit S (aqueous dispersion)>Eudragit FS>Eudragit S (organic solution). The results indicate that the tablets coated with the newer Eudragit FS polymer would be more appropriate for drug delivery to the ileo-colonic region in comparison to the more established Eudragit S. More importantly, however, dissolution in the physiological buffer was found to be markedly slower for all the coated tablets than in the two compendial buffers, a result akin to reported slower dissolution of enteric coated tablets in vivo. There is therefore the need to adequately simulate the ionic composition of the intestinal fluid in the dissolution media.     

Ethylcellulose microparticles: a review

Ethylcellulose (EC) based microencapsulated drug delivery systems are being extensively studied throughout the world for achieving extended drug release and protecting the core substance from degradation. The in vitro evaluation of EC microcapsules have elucidated that their particle characteristics are very useful to control drug release behavior, since these enable drugs to be released at a certain controlled release rate based on the characteristics of drug-EC linkage. This review encompasses microencapsulation techniques, core substances and other fundamentals involved in the preparation and characterization of EC microcapsules. EC microcapsules can be considered as mini-osmotic pumps. The release kinetics for EC microcapsules can be fine-tuned by altering osmolality of the dissolution medium or formulations and EC film mechanical characteristics by selecting appropriate EC molecular weights (viscosity), EC substitution grades, coating weights, and pore formers.     

Development of a novel osmotically driven drug delivery system for weakly basic drugs

The drug substance SAG/ZK has a short biological half-life and because of its weakly basic nature a strong pH-dependent solubility was observed. The aim of this study was to develop a controlled release (cr) multiple unit pellet formulation for SAG/ZK with pH-independent drug release. Pellets with a drug load of 60% were prepared by extrusion/spheronization followed by cr-film coating with an extended release polyvinyl acetate/polyvinyl pyrrolidone dispersion (Kollidon SR 30 D). To overcome the problem of pH-dependent drug release the pellets were then coated with a second layer of an enteric methacrylic acid and ethyl acrylate copolymer (Kollicoat MAE 30 DP). To increase the drug release rates from the double layered cr-pellets different osmotically active ionic (sodium and potassium chloride) and nonionic (sucrose) additives were incorporated into the pellet core. Drug release studies were performed in media of different osmotic pressure to clarify the main release mechanism. Extended release coated pellets of SAG/ZK demonstrated pH-dependent drug release. Applying a second enteric coat on top of the extended release film coat failed in order to achieve pH-independent drug release. Already low enteric polymer levels on top of the extended release coated pellets decreased drug release rates at pH 1 drastically, thus resulting in a reversal of the pH-dependency (faster release at pH 6.8 than in 0.1N HCl). The addition of osmotically active ingredients (sodium and potassium chloride, and sucrose) increased the imbibing of aqueous fluids into the pellet cores thus providing a saturated drug solution inside the beads and increasing drug concentration gradients. In addition, for these pellets increased formation of pores and cracks in the polymer coating was observed. Hence drug release rates from double layered beads increased significantly. Therefore, pH-independent osmotically driven SAG/ZK release was achieved from pellets containing osmotically active ingredients and coated with an extended and enteric polymer. In contrast, with increasing osmotic pressure of the dissolution medium the in vitro drug release rates decreased significantly.     

Microencapsulation of theophylline in composite wall system consisting of whey proteins and lipids

Theophylline was microencapsulated in composite whey protein-based wall systems containing different proportions of dispersed apolar filler, anhydrous milkfat. Wall emulsions exhibited uni-modal particle size distribution and had a mean particle size of 0.36-0.38 microm. Microcapsules were cross-linked by glutaraldehyde-saturated toluene via an organic phase. Spherical microcapsules ranging in diameter from 150 to larger than 700 microm were obtained and exhibited some surface cracks that could be attributed to the fragile nature of a peripheral, highly cross-linked 'shell' layer around the capsules. Core content ranged from 46.9-56.6% (w/w) and filler content ranged from 12.0-33.4% (w/w). Core and filler retention during microencapsulation ranged from 84.9-96.9%) and from 85.1-89.6%, respectively. Core retention was proportionally related to the proportion of filler embedded in the wall matrix. Core release into SGF and SIF was affected by microcapsule size, type of dissolution medium and wall composition. Rate of core release was inversely proportional to filler content of the wall matrix. This could be attributed to effects of filler content on diffusion through the wall matrix and probably on swelling properties of microcapsules. Results indicated that incorporation of apolar filler in wall matrix of whey protein-based capsules provided the means to enhance retention of a water-soluble core during the microencapsulation process and to decrease the rate of core release into aqueous dissolution media.     

Effect of ethylcellulose grade and sealant treatments on the production and in vitro release of microencapsulated sodium salicylate

Sodium salicylate was microencapsulated with ethylcellulose 100 cp by polymer deposition from cyclohexane by temperature change to give a finer product, with slower drug release, than that obtained with 10 cp grade of ethylcellulose. Scanning electron microscope and polymer disc swelling studies confirmed that larger microcapsules after drug release ruptured into smaller particles with swollen surfaces containing pores. Treatment of microcapsules with paraffin wax solution retarded release of core material, the release being affected by the percentage of sealant used and the particle size of the product. The mechanism of release from the sealed microcapsules was complex involving mainly diffusion, but polymer erosion and drug binding were also involved. Other sealant materials were less effective in retarding dissolution.     

Dissolution studies of microencapsulated indomethacin; effect of method and medium on dissolution

In vitro dissolution studies of microencapsulated indomethacin showed that the USP paddle method was superior to the USP basket method in that the drug release was higher and more uniform with the paddle. Simulated intestinal fluid (pH 7.2) was an appropriate medium to use for dissolution studies on prolonged-release microcapsules.     

吡哌酸缓释微囊的体外溶出特性考察

考察了不同主药含量、不同粒径的吡哌酸缓释微囊的药物溶出特性及在不同pH介质中的溶出行为,探讨了微囊中吡哌酸含量对微囊结构、半数测出时间T_(50)及药物渗透性的影响与因不同pH介质中由于药物溶解度不同而引起的溶出行为的改变。证实了微囊释药符合Higuchi方程,其结构与药物含量有关,药物渗透性及T_(50)~(1/2)与药物含量存在线性相关性,药物溶出因微囊粒径减小、药物于介质中溶解度增加而增加。     

Microencapsulation of theophylline in composite wall system consisting of whey proteins and lipids

Theophylline was microencapsulated in composite whey protein-based wall systems containing different proportions of dispersed apolar filler, anhydrous milkfat. Wall emulsions exhibited uni-modal particle size distribution and had a mean particle size of 0.36-0.38 µm. Microcapsules were cross-linked by glutaraldehyde-saturated toluene via an organic phase. Spherical microcapsules ranging in diameter from 150 to larger than 700 µm were obtained and exhibited some surface cracks that could be attributed to the fragile nature of a peripheral, highly cross-linked 'shell' layer around the capsules. Core content ranged from 46.9-56.6% (w/w) and filler content ranged from 12.0-33.4% (w/w). Core and filler retention during microencapsulation ranged from 84.9-96.9% and from 85.1-89.6%, respectively. Core retention was proportionally related to the proportion of filler embedded in the wall matrix. Core release into SGF and SIF was affected by microcapsule size, type of dissolution medium and wall composition. Rate of core release was inversely proportional to filler content of the wall matrix. This could be attributed to effects of filler content on diffusion through the wall matrix and probably on swelling properties of microcapsules. Results indicated that incorporation of apolar filler in wall matrix of whey protein-based capsules provided the means to enhance retention of a water-soluble core during the microencapsulation process and to decrease the rate of core release into aqueous dissolution media.     

Influence of coacervation-inducing agents and cooling rates on the preparation and in vitro release of bleomycin hydrochloride microcapsules

Abstract

Two types of coacervation-inducing agents (EVA, PIB) and three cooling rates (0.01998, 0.03482 and 0.06725d`C/min) affecting the preparation, micromeritic and drug release properties of bleomycin hydrochloride microcapsules were investigated. Particle size distribution of microcapsules induced by EVA significantly depended on the cooling rate, but that induced by PIB was independent of the cooling rate. Higher viscosity of PIB led to a smaller particle size of microcapsules than when EVA was used. The surface topography of the microcapsules for both types of coacervation-inducing agents was obviously different. We found that the release behaviour of bleomycin hydrochloride from the microcapsules also depended on the type of coacervation-inducing agent and the cooling rate. In general, the slower the cooling rate the more prolonged the release of the drug. Higuchi matrix model was followed for bleomycin hydro chloride released from the microcapsules. T₅₀ of both types of microcapsules decreased with the increase of the cooling rate. To simulate the absorption behaviour of the GI tract, the continuous flow dialysis method was modified for drug release from the microcapsules. The data indicate that the diffusion of the dissolution medium and dissolved drug through the ethylcellulose wall of the microcapsules is the rate-limiting step before dialysis. This also implies that the release rate of the drug from dosage form significantly determined the absorption in the GI tract.     

In vitro-in vivo evaluation of bacampicillin hydrochloride from microcapsules of water-insoluble and an acid-soluble polymer

Bacampicillin hydrochloride has been microencapsulated to mask its very bitter taste. The objective of the study was to compare the in vitro release and bioavailability of bacampicillin hydrochloride from microcapsules coated with two principally different polymers: a water-insoluble polymer, ethylcellulose, and an acid-soluble polymer, Eudragit E 100. The last mentioned was supposed to have advantages from a bioavailability point of view since this polymer should dissolve rapidly upon reaching the stomach. In vitro release studies were performed in different types of media by using a flow-through cell technique and USP paddle apparatus. The in vivo study was performed on 20 healthy volunteers taking single 400 mg doses of the drug in the two microcapsule suspensions and a reference tablet according to a randomized cross-over design. When standard dissolution fluids were used, the Eudragit E 100-coated microcapsules revealed very rapid dissolution but were greatly dependent on buffer concentration and ionic strength. The ethylcellulose-coated microcapsules released the drug much more slowly than Eudragit E 100 when using standard dissolution fluids. They were also affected by buffer concentration and ionic strength. The reference tablet had a significantly higher bioavailability than the two microcapsule suspensions. In vitro-in vivo correlation was not obtained when using standard dissolution fluids according to USP. However when stimulated intestinal fluid was adjusted to have an ionic strength similar to intestinal fluid, a better in vitro-in vivo correlation was obtained. The Eudragit E 100 polymer did not give better bioavailability than ethylcellulose as a coating polymer on bacampicillin microcapsules.     

Controlled release captopril microcapsules: effect of non-ionic surfactants on release from ethyl cellulose microcapsules

Captopril microcapsules were prepared with different viscosity grades of ethyl cellulose by temperature induced coacervation from cyclohexane. Both non-ionic surfactants or their combinations and 2 per cent absolute alcohol as cosolvent were added to the coacervation system to ensure complete solvation of the ethyl cellulose and efficient microencapsulation of the drug. The in vitro dissolution was studied in 0.1 N hydrochloric acid. Microcapsules prepared using 2 per cent Tween 80 with ethyl cellulose of 41 c.p. viscosity grade exhibited the most prolonged release with a t70 per cent of 55 min in comparison to 7.75 min for control microcapsules prepared without surfactant. Different kinetic models have been used to explain the release. The best fit with the highest correlation coefficients was the first-order kinetics plot with two straight lines having two different slopes. The initial slope presents the faster release rate than the terminal slope. This fast release would be useful for the initial dose of the prolonged release formulation.     

Dual ambroxal and chlorpheniramine resinate as an alternative carrier in concurrent resinate administration

Two classical resinates, ambroxal (AMX) resinate and chlorpheniramine (CPM) resinate, and a novel formulation of dual AMX and CPM resinate were prepared by the batch method. The dissolution behavior of the drug from the classical resinates, a mixture of two classical resinates, and the dual-drug resinate in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) was examined and compared. The equilibrium of drug on to the resin and the re-exchange of the drug on to the resinate were also investigated. The drug release pattern from the resinate followed the particle diffusion process. The type of dissolution medium affected the amount of drug released from the resinate. The amount of drug released from the dual AMX and CPM resinate was not significantly different from that from the classical AMX resinate or CPM resinate (p < 0.05), but was considerably higher than that from the concurrent administration of two classical resinates (p > 0.05). These results indicated that the concurrent administration of the resinates affected drug release from the resinate, and the dual-drug resinate can be used as an alternative carrier for an ion-exchange delivery system.     

5-氨基水杨酸结肠定位给药时控微丸的制备与体外释放

目的　用水分散体包衣技术制备5-氨基水杨酸结肠定位微丸给药系统。方法　以低粘度HPMC为内层溶胀材料,乙基纤维素水分散体Aquacoat为外层控释包衣材料,柠檬酸三乙酯为增塑剂,使用流化床包衣设备,制备时间控制的微丸,用释放度测定法研究微丸在不同pH介质中的释放度。结果　溶胀层的加入对制备时控微丸是必要的,药物是通过外膜破裂释放的,溶胀层厚度增加,释药时滞有一定程度的缩短,外层厚度增加以及增塑剂用量增加,可显著延长释药时滞。微丸释药随介质pH增加而加快,在模拟胃肠道pH情况下延迟5 h释药,之后10 h内释药完全。结论　通过调整内外层的包衣厚度可制备5-氨基水杨酸结肠定位给药微丸。     

Controlled release captopril microcapsules: effect of ethyl cellulose viscosity grade on the in vitro dissolution from microcapsules and tableted microcapsules

Captopril microcapsules were prepared using four different viscosity grades of ethyl cellulose (core: wall ratios 1:1, 1:2 and 1:3) by temperature induced coacervation from cyclohexane. In vitro dissolution studies in 0.1 M hydrochloric acid showed that the drug release was dependent on the core to wall ratio, the viscosity grade of the ethyl cellulose and thus the total viscosity of the coacervation system. Viscosity grade of greater than 100 c.p. was unsuitable for microencapsulation by coacervation method at the concentration used. The surface characteristics of a 1:2 core to wall ratio were studied by scanning electron microscopy. The surface of the microcapsules prepared with 10 c.p. viscosity grade was comparatively more porous with larger size pores than 50 c.p. viscosity grade of ethyl cellulose. However, 300 c.p. viscosity grade showed incomplete wall formation. The microcapsules did not fragment during dissolution, alter in shape or size, or show evidence of enlargement of the surface pores. The tensile strength of tablets prepared at constant pressure from each batch of microcapsules (mean diameter 675 microns) increased as both the core to wall ratios and the viscosity of ethyl cellulose increased. The dissolution rate of the drug from tableted microcapsules was significantly delayed. The in vitro release gave best correlation with first order release kinetics when compared to zero-order and square-root-of-time equations.